European Patent Application No. 88307985.7 discloses azolidinedione derivatives useful as hydantoin aldose reductase inhibitors. These compounds are useful in the treatment of certain chronic complications arising from diabetes mellitus, such as cataracts, retinopathy and neuropathy. European Patent Application No. 85307712.1 discloses the preparation of these compounds via dichloromalonoaldehyde intermediates. The alternative synthesis of the present invention is advantageous because it avoids the use of dichloromalonoaldehyde which is a known mutagen. The present synthesis also produces azatetralones in a chiral form.
Carbon-carbon bond formation by cross coupling of Grignard reagents with organic halides mediated by catalysts such as 1,2-bis(diphenylphosphino)ethane nickel (II) (dppe) and 1,3-bis(diphenylphosphino)propane nickel (II) chloride (dppp) has been shown in a variety of systems including arenes, furans, thiophenes, pyridines, and quinolines. (K. Tamao, et al., Tetrathedron, 38, No. 22, pp. 3347-3354 (1982)). While single and double displacements of aromatic halogens with Grignard reagents and the aforementioned nickel/phosphine ligands has been shown, regiospecific displacement of one halogen in a polyhalogenated aromatic ring system had not been accomplished.
Ring systems have also been assembled, by so-called Parham cyclization involving low temperature transmetallation of a halogen, often bromine, with n- or t-butyllithium and subsequent intramolecular cyclization (Parham, W. E. et al., 40 J.O.C. 2394 (1975); Parham, W. E. et al., Acc. Chem., Res., 15, 300 (1975); and Snieckus, V. et al., Tett. Lett. 2933 (1987)). The electrophiles in this approach have included carboxylic acids, halogens, epoxides, and Schiff bases.